New Australian data show high VCAM-1 levels identify a vascular-cardiac, rather than fibrotic, phenotype in scleroderma.
High circulating levels of vascular cell adhesion molecule-1 (VCAM-1) appear to identify a distinct vascular subtype of systemic sclerosis associated with substantially higher mortality, according to Australian researchers who say the biomarker could improve risk stratification in the disease.
The study, published in Rheumatology, found that patients with the highest serum VCAM-1 concentrations were more than twice as likely to die as those with lower levels, with the excess mortality driven by pulmonary arterial hypertension (PAH), systemic sclerosis-attributable myocardial disease, and cardiovascular complications rather than interstitial lung disease (ILD).
However, the work does not label VCAM-1 as a new biomarker. Elevated VCAM-1 has long been recognised as a marker of endothelial activation in systemic sclerosis, and the Australian research group previously reported it as the strongest mortality-associated biomarker in a panel of 27 serum markers.
The new study refines that finding by demonstrating that the mortality signal appears to reflect a predominantly “vasculopathic” phenotype rather than fibrotic lung disease.
The researchers, including Dr Matthew Parker, Professor Mandana Nikpour, Professor Susanna Proudman, and members of the Australian Scleroderma Interest Group, analysed 388 patients enrolled in the Australian Scleroderma Cohort Study, a national multicentre longitudinal registry established in 2007.
The cohort was predominantly female (87.1%), with three-quarters having limited cutaneous systemic sclerosis. Clinical data were linked with the National Death Index, while serum VCAM-1 concentrations were measured using magnetic Luminex assays.
Participants were followed until February 2024 and stratified into quartiles according to VCAM-1 level. Median VCAM-1 concentration across the cohort was 414.7ng/mL.
Patients in the highest quartile had levels exceeding 537ng/mL. These patients experienced significantly poorer survival, with a hazard ratio for all-cause mortality of 2.17 compared with the lower three quartiles.
An independent validation cohort of 247 patients confirmed the association, with elevated VCAM-1 remaining predictive of mortality after adjustment for age, sex, pulmonary arterial hypertension, and ILD.
Notably, patients with high VCAM-1 did not differ from other participants in many of the factors traditionally associated with poor prognosis in systemic sclerosis.
There were no significant differences in age at diagnosis, disease duration, diffuse versus limited cutaneous disease, autoantibody profile, forced vital capacity, conventional cardiovascular risk factors, or previous malignancy, suggesting VCAM-1 provides prognostic information beyond established clinical markers.
Instead, elevated VCAM-1 was closely linked with vascular manifestations.
Patients in the highest quartile were significantly more likely to have right heart catheter-confirmed pulmonary arterial hypertension before baseline, with higher pulmonary artery pressures on echocardiography, higher NT-proBNP concentrations, and more frequent use of PAH-targeted therapies. They also had almost double the prevalence of systemic sclerosis-associated myocardial disease, were substantially more likely to have experienced digital ulceration and had a higher prevalence of scleroderma renal crisis.
By contrast, VCAM-1 showed no relationship with clinician-defined or HRCT-confirmed interstitial lung disease, ILD severity, or ILD-related mortality, despite ILD remaining one of the leading causes of death in systemic sclerosis. Researchers suggested this indicates VCAM-1 reflects vascular pathology rather than fibrotic processes.
Cause-of-death analysis reinforced the finding.
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Among participants with linked mortality data, those with VCAM-1 levels in the highest quartile had a threefold increase in PAH-related mortality (HR 3.08), almost threefold higher mortality attributable to systemic sclerosis myocardial disease (HR 2.85) and a 2.5-fold increase in all cardiovascular mortality. No significant increase was observed for ILD-related deaths.
The researchers said the combination of pulmonary arterial hypertension, myocardial disease, and digital ulceration formed a recognisable vascular phenotype that may explain why VCAM-1 has consistently emerged as such a powerful predictor of survival.
“High baseline VCAM-1 was associated with the triad of serious vascular complications in systemic sclerosis, namely pulmonary arterial hypertension, myocardial disease and digital ulceration,” the researchers wrote.
“This study replicates and helps validate recent findings of VCAM-1 and high mortality in SSc. There is a strong case for further work to determine whether VCAM-1 can refine prognosis or illuminate vasculopathic mechanisms in SSc.”
The researchers acknowledged several limitations, including that the cohort largely comprised patients with longstanding, predominantly limited systemic sclerosis, introducing potential selection and survivor bias.
Serum sampling was opportunistic rather than event-driven, cause-of-death coding relied on ICD-10 classifications, and no healthy control group was included to establish a normal reference range for VCAM-1.
“Our data do not establish that VCAM-1 is prognostic of developing SSc organ manifestations or that it is causally linked to the various mortality outcomes but, in our opinion, do demonstrate a clear rationale for further work,” they wrote.
